The long-term functional implication of in utero and postnatal highly active antiretroviral therapy (HAART) exposures for perinatally human immunodeficiency virus (HIV) exposed or infected children in school-age and beyond is unknown. Recent data from the US pediatric HIV/AIDS Cohort Study (PHACS) finds that perinatally HIV exposed and perinatally HIV infected children have cognitive test scores in the low range of normal but did not find significant cognitive deficit for HIV-exposed unexposed children with and without in utero HAART. Almost no data on this subject is available for children from sub-Saharan Africa where an estimated 1.4 million children per year are exposed to iatrogenic HAART during sensitive periods of neural, physical and social development. Perinatally HIV exposed or infected children contend with a steady stream of physiologic and psychosocial stressors in utero, early childhood and throughout their life course. These stressors occur during sensitive periods of development and may be associated with medium to long-term functional deficits. For example, academic achievement and psychosocial adjustment represent common standards by which individual success is measured in childhood and adolescence. Appropriate development in these areas is closely linked to overall academic attainment and future capacity to productively contribute to the society as an adult. For perinatally HIV infected adolescents, there is a simultaneous exectation that they progressively take charge of managing their chronic health condition through consistent adherence to HAART regimen and gaining competence in navigating the healthcare system. These capacities require a robust executive cognitive function and appropriate psychosocial adjustment. To inform knowledge gaps, and contribute new data on long-term differences in functional outcomes (i.e. cognitive development, psychosocial adjustment and quality of life) for perinatally HIV exposed and infected compared to perinatally HIV unexposed children, we evaluate HIV status related differences in functional outcomes in a cohort of 11-18 years old Ugandan children with and without perinatal HIV exposure/infection. We specifically assess psychosocial and physiologic stress ? measured as a composite of dysregulations across multiple organ systems, as mediators of any HIV-related deficits in functional impairment. By design we distinguish between functional outcomes for HIV exposed or infected children in comparison to perinatally HIV unexposed children from the same community. This study is therefore positioned to provide a comprehensive and robust assessment of HIV specific impact on functional indicators in school-age and adolescence. Data arising from this investigation will inform the nature of possible remedial interventions required to optimize the long-term functional status of perinatally HIV exposed or infected children and adolescents.